EP0994851B1

EP0994851B1 - Process for the preparation of 2-alkylthio benzoic acid derivatives

Info

Publication number: EP0994851B1
Application number: EP98940255A
Authority: EP
Inventors: Didier Bernard; Agnès Viauvy
Original assignee: Bayer CropScience SA
Current assignee: Bayer CropScience SA
Priority date: 1997-07-07
Filing date: 1998-07-03
Publication date: 2004-02-18
Anticipated expiration: 2018-07-03
Also published as: TW588035B; CN1262673A; EP0994851A1; ES2212331T3; DE69821763D1; KR20010021608A; ZA985767B; IL133816A0; CA2295912A1; GB9714302D0; CN1176071C; JP2001509501A; DE69821763T2; HUP0003059A3; BR9810686A; PL337906A1; AU8863498A; US6777575B2; US20020103396A1; HUP0003059A2

Abstract

A process for preparing a compound of the formulacomprising reacting a compound of the formulawherein R3 is nitro or halo, or a salt thereof, with a compound of the formula R1SX (III) wherein X is hydrogen or alkali metal.

Description

This invention relates to a process for preparing certain 2-alkylthio substituted benzoic acid derivatives and their salts, which are useful as intermediates in the preparation of herbicidally active compounds.
European Patent Publication No. 527036 discloses 2-methylthio-4-trifluoromethylbenzoic acid and a preparation for it. However the method described employs organolithium reagents at low temperatures which are unsuitable for large scale preparations.
The reaction to prepare 4-alkylthiosubstituted benzoate esters by the reaction of 4-halo-benzoate esters with alkyl mercaptans is known, for example as described in US Patent Nos. 1,453,885 and 5,092,919. The corresponding reaction to prepare 4-alkylthio substituted benzoic acids by the reaction of 4-chlorobenzoic acids with alkyl mercaptans is also known, for example as reported by Beck and Yahner in J. Org. Chem. 43(10), 2052 (1978), Japanese Patent J5 8198-464 and US Patent No. 1,453,885.
Reactions to prepare 2-alkylthio-substituted benzoic acid esters are also known for example as described in EP0560482 and W09531446. EP0780371 also discloses the preparation of 2-alkylthio-4-trifluoromethylbenzoic acid esters. However, to the applicants knowledge there are only two references which report the displacement of a 2-halo group by alkyl mercaptans to give 2-alkylthio substituted benzoic acids, and neither of these reactions is performed using the benzoic acid as reactant. Thus F.Ruff et al. in Tetrahedron Volume 34, 2767 (1978) describes the preparation of 2-methylthio-5-nitrobenzoic acid by the reaction of methyl mercaptan with methyl 2-chloro-5-nitrobenzoate in the presence of base. In this case the 2-chlorine atom is very highly activated by the presence of the 5-nitro group. The second reference US Patent No. 3,714,179 illustrates the difficulty of displacement of the 2-fluorine atom in ethyl 2-fluorobenzoate, with the product ethyl 2-methylthiobenzoate being obtained after heating for a 3 week period.
It is desirable to provide intermediates which are used in multistep synthetic sequences in high yields and also to develop new procedures which allow the efficient displacement of 2-halo or 2-nitro-substituted benzoic acids and their salts and esters to furnish 2-alkylthio substituted benzoic acids and their salts and esters.
It is therefore an object of this invention to provide a process for preparing 2-alkylthio substituted benzoic acids and their salts proceeding in high yield, and requiring a short reaction period. The present invention allows this object to be met in whole or in part.
Thus, the present invention provides a process for the preparation of a compound of formula (I):
wherein R represents hydrogen;
R₁ represents C_1-6 alkyl;
R₂ represents C_1-6 haloalkyl, C_1-6 alkyl, C_1-6 haloalkoxy, C_1-6 alkoxy, SO_nR₅ or halogen;
R₄ represents hydrogen, C_1-6 haloalkoxy, C_1-6 alkoxy, SO_nR₅ or halogen; or a 5 or 6-membered heterocyclic ring (which may be unsaturated or partially saturated) containing 1 to 3 hetero atoms selected from oxygen, nitrogen and sulphur, optionally substituted by halogen, C_1-6 haloalkyl, C_1-6 alkyl, C_1-6 haloalkoxy, C_1-6 alkoxy, SO_nR₅, nitro or cyano;
R₅ represents C_1-6 alkyl; and
n represents 0, 1 or 2;
or a salt thereof; which process comprises the reaction of a compound of formula (II):
wherein R, R₂ and R₄ are as hereinbefore defined, and R₃ represents nitro or a halogen atom selected from fluorine, chlorine and bromine; or a salt thereof, with a compound of formula (III): R₁SX wherein R₁ is as hereinbefore defined, and X represents hydrogen or an alkali metal, wherein the reaction is performed with less than 1% by volume water content.
When R₄ represents a heterocyclic ring, preferred rings include 3-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 5-oxazolyl, 2-furyl, 3-furyl, 2-thienyl and 3-thienyl.
R represents hydrogen.
R₁ preferably represents methyl.
R₂ preferably represents trifluoromethyl.
R₃ preferably represents fluorine or chlorine.
R₄ preferably represents hydrogen.
X preferably represents hydrogen or a sodium, potassium or lithium atom.
When salts are used in the above reaction, preferably the salts are alkali metal salts.
In an especially preferred embodiment of the invention R₁ represents C_1-6 alkyl (methyl is most preferred);
R₂ represents C_1-6 haloalkyl (trifluoromethyl is most preferred);
R₃ represents a halogen atom selected from fluorine, chlorine and bromine (fluorine or chlorine are most preferred); and
R₄ represents hydrogen.
The reaction of a compound of formula (II) with a compound of formula (III) is performed with less than 1% by volume water content, i.e. under anhydrous conditions. It has been found that the reaction proceeds in excellent yield under such conditions.
Generally the reaction takes place with from 0.005 to 0.05% by volume water. It will however be understood that in certain cases slightly more or less water may be tolerated, depending on the nature of the solvents used and the temperature of the reaction, the compound of formula (I) or salt thereof to be prepared and other reaction conditions.
The reaction may be carried out using a number of solvents, but is preferably performed in a polar aprotic solvent for example N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, acetonitrile or dimethylsulphoxide. Preferred solvents are N-methylpyrrolidinone, acetonitrile or dimethylsulphoxide, the former two being preferred when the process is performed on a large scale, for reasons of cost and availability.
Where X is hydrogen, a base is preferably also present in the reaction mixture. Examples of suitable bases are alkali metal carbonates, alkoxides or hydrides such as potassium carbonate, potassium t-butoxide or sodium hydride, or amidine bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,1,3,3-tetramethylguanidine.
The reaction is generally performed at a temperature from -20°C to 150°C. For compounds of formula (II) wherein R represents hydrogen or an alkali metal, a temperature of from 50°C to 100°C is preferred.
The molar ratio of the benzoic acid derivative of formula (II): alkyl thiol of formula (III) is generally from 1:1 to 1:2, preferably from 1:1 to 1:1.5, even more preferably from 1:1.05 to 1:1.3.
In one embodiment of the above reaction to prepare compounds of formula (I) from compounds of formula (II), R represents hydrogen or the compound of formula (II) is used in the form of a salt, preferably an alkali metal salt.
Compounds of formula (II) and (III) above are known in the literature or can be prepared using known methods.
The following non-limiting examples illustrate the invention.

Example 1

Preparation of 2-methylthio-4-trifluoromethylbenzoic acid

A mixture of anhydrous sodium thiomethoxide (0.39g, 0.00525M), 2-chloro-4-trifluoromethylbenzoic acid sodium salt (1.23g, 0.005M) and anhydrous N-methylpyrrolidinone (10ml, containing less than 0.01% of water) was heated at 90°C for 2 hours. The mixture was cooled to 20°C, acidified and extracted (t-butyl methyl ether). The extract was washed (water) and evaporated to give 2-methylthio-4-trifluoromethylbenzoic acid (1.18g, 100% yield), ¹H-nmr 2.40(s,3H), 7.30(1H), 7.38(1H), 8.07(1H). The purity of the product was greater than 95%.
By proceeding as described above but using dimethylsulphoxide instead of N-methylpyrrolidinone there was obtained 2-methylthio-4-trifluoromethylbenzoic acid in 99% yield (purity >95%).
By proceeding as described above but using a 9:1 mixture of acetonitrile and N-methylpyrrolidinone instead of N-methylpyrrolidinone alone, there was obtained 2-methylthio-4-trifluoromethylbenzoic acid in 97% yield (purity greater than 95%).

Example 2

The effect of the presence of water in the reaction mixture was analysed in the following experiment. The conditions of Example 1 were repeated at 100°C but using 1.3 equivalents of sodium thiomethoxide and N-methylpyrrolidinone as solvent containing the percentages of water (by volume) shown in Table 1.

% Water Temperature % Yield

20 100°C 12

1 80°C 79

0.01 90 °C 100
The above results indicate that increasing concentrations of water leads to a decreasing yield of product.

Example 3

The effect of temperature was examined by repeating the conditions of Example 1 at various temperatures. Table 2 shows the results for two sets of reactions, one set where 0.01% water was present and the other where 2% water was present:

2% Water	Anhydrous (0.01% water)
Temperature	Yield	Temperature	Yield
60 °C	3%	80 °C	91%
80°C	52%	90 °C	100%
100 °C	65%	-(1)	-(1)
Note (1): this experiment was not performed.

The above experiments therefore clearly demonstrate the advantage of the process of the invention over the prior art, thereby providing access to valuable intermediates in higher yield and shorter reaction period.
The compounds obtained by the process of the present invention may be used in the preparation of herbicidally active compounds as described, for example, in European Patent Publication Nos. 0418175, 0527036 and 0560482.

Claims

A process for the preparation of a compound of formula (I):
wherein R represents hydrogen;
R₁ represents C_1-6 alkyl;
R₂ represents C_1-6 haloalkyl, C_1-6 alkyl, C_1-6 haloalkoxy, C_1-6 alkoxy, SO_nR₅ or halogen;
R₄ represents hydrogen, C_1-6 haloalkoxy, C_1-6 alkoxy, SO_nR₅ or halogen; or a 5 or 6-membered heterocyclic ring (which may be unsaturated or partially saturated) containing 1 to 3 hetero atoms selected from oxygen, nitrogen and sulphur, optionally substituted by halogen, C_1-6 haloalkyl, C_1-6 alkyl, C_1-6 haloalkoxy, C_1-6 alkoxy, SO_nR₅, nitro or cyano;
R₅ represents C_1-6 alkyl; and
n represents 0, 1 or 2;
or a salt thereof; which process comprises the reaction of a compound of formula (II):
wherein R, R₂ and R₄ are as hereinbefore defined, and R₃ represents nitro or a halogen atom selected from fluorine, chlorine and bromine; or a salt thereof, with a compound of formula (III): R₁SX wherein R₁ is as hereinbefore defined, and X represents hydrogen or an alkali metal, wherein the reaction is performed with less than 1% by volume water content.
A process according to claim 1 which is performed in an aprotic solvent.
A process according to claim 2 wherein the aprotic solvent is N-methylpyrrolidinone, acetonitrile or dimethylsulphoxide.
A process according to any one of claims 1 to 3 in which the molar ratio of the benzoic acid derivative of formula (II): alkyl thiol of formula (III) is from 1:1 to 1:2.
A process according to any one of claims 1 to 4 in which R₁ represents C_1-6 alkyl, R₂ represents C_1-6 haloalkyl and R₄ represents hydrogen.
A process according to any one of claims 1 to 5 in which R₁ represents methyl, R₂ represents trifluoromethyl and R₄ represents hydrogen.